1. Field of the Invention
The invention is generally related to the therapeutic use of xcex949 Tetrahydrocannabinol (xcex949 THC). In particular, the invention provides a metered dose inhaler (MDI) for the aerosol administration of xcex949 THC to patients suffering from nausea and vomiting associated with cancer chemotherapy, muscle spasticity, pain, anorexia associated with AIDS wasting syndrome, epilepsy, glaucoma, bronchial asthma, mood disorders, and the like.
2. Background Description
xe2x80x9cMedical Marijuanaxe2x80x9d is a timely and controversial subject that is currently receiving widespread public attention. While marijuana is usually thought of as an illegal xe2x80x9crecreationalxe2x80x9d drug, it also has a long history as a medicine. In 1997, the National Institutes of Health (NIH) released a review of the scientific data concerning potential therapeutic uses for marijuana. In that review, the NIH found that marijuana may indeed have beneficial medicinal effects and recommended that researchers develop alternative dosage forms for the drug, such as a xe2x80x9csmoke freexe2x80x9d inhaled delivery system (1). Table 1 summarizes the findings of several studies (references 2-18) that have documented therapeutically beneficial medicinal uses of the major active component of marijuana, xcex949 tetrahydrocannabinol (xcex949 THC).
When marijuana is used illegally as a recreational psychoactive drug, the active ingredient xcex949 THC is usually delivered to the lungs as an impure non-pharmaceutical aerosol in the form of marijuana smoke. Aerosolized xcex949 THC in the inhaled smoke is absorbed within seconds and delivered to the brain efficiently. Table 2 and references 19-20 describe the pharmacokinetics of the administration of xcex949 THC. As can be seen, inhalation is the preferred route of delivery for xcex949 THC. When compared to oral delivery, inhalation provides a more rapid onset of pharmacological action and peak plasma levels. The effects achieved via inhalation are comparable to those achieved when the drug is administered intravenously, but inhalation is a much less invasive technique.
Currently, the sources of xcex949 THC for patients who could benefit from the drug are very limited. An oral form of xcex949 THC (MARINOL) is marketed as a treatment for nausea and vomiting related to cancer chemotherapy, and as an appetite stimulant in patients suffering from AIDS wasting syndrome. In MARINOL, pharmaceutical grade xcex949 THC is dissolved in sesame oil, encapsulated in gelatin capsules and delivered orally. However, when the drug is taken orally, the absorption is slower and more variable than when inhaled, with an onset of action between 30 minutes and 2 hours (Table 2). Alternatively, some cancer patients do manage to obtain and smoke marijuana in order to alleviate such conditions as nausea and vomiting due to chemotherapy. This is, however, technically illegal and is thus obviously a less than ideal treatment protocol. There is no currently available pharmaceutically acceptable aerosol form of xcex949 THC.
It would be advantageous to have available a form of pharmaceutical grade xcex949 THC that could be administered as an aerosol. This would provide a means for rapid uptake of the drug without resorting to the illegal practice of smoking marijuana. Also, the potential adverse side effects encountered by smoking marijuana would be avoided. Further, an aerosol preparation of pharmaceutically pure xcex949 THC could be administered in known, controlled dosages.
In 1976, Olsen et al. described a chlorofluorocarbon (CFC) propelled MDI formulation of xcex949 THC (21). However, xcex949 THC is known to deteriorate during storage, and the stability of xcex949 THC in this formulation is suspect. In addition, the ethanol content in this formulation was so high (xcx9c23%) as to create an aerosol with droplets too large to be effectively inhaled (22). The xcex949 THC CFC formulations were tested for use in treating asthma but were shown to be only moderately effective (23, 24). Moreover, CFC propellants have since been banned so that such a formulation is now useless. It would clearly be advantageous to develop a new aerosol formulation in which the xcex949 THC is stable, the droplets are of a size that can be effectively inhaled, and which utilizes a non-CFC propellant.
It is an object of the present invention to provide a stable aerosol-dispensable pharmaceutical composition comprising a non-CFC propellant and a pharmaceutically effective concentration of xcex949 THC. More particularly, it is an object of the present invention to provide a stable aerosol-dispensable pharmaceutical composition comprising a hydrofluoroalkane propellant, (for example, HFA 227 or HFA 134a) and xcex949 THC. The propellant is present in the range of approximately 78 to 100% by weight, and more particularly the propellant is present in the range of approximately 85 to 100% by weight. An organic solvent such as ethanol can be used to assist in solubilizing the xcex949 THC in the propellant but is not required. If a solvent is used, preferably less than 20% by weight will be required, and most preferably less than 15% by weight will be required. The pharmaceutically effective concentration of xcex949 THC is preferably in the range of 0.05 to 10% by weight, and most preferably in the range of 0.1 to 6% by weight. The pharmaceutical composition of the present invention can be used to treat a variety of medical conditions including nausea and vomiting associated with cancer chemotherapy, muscle spasticity, pain, anorexia associated with AIDS wasting syndrome, anorexia associated with cancer chemotherapy, epilepsy, glaucoma, bronchial asthma, mood disorders, migraine headaches.